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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 67, NO. 3, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2015.11.034
THE PRESENT AND FUTURE
COUNCIL PERSPECTIVES
Exercise at the Extremes
The Amount of Exercise to Reduce Cardiovascular Events
Thijs M.H. Eijsvogels, PHD,*y Silvana Molossi, MD, PHD,z Duck-chul Lee, PHD,x Michael S. Emery, MD,k
Paul D. Thompson, MD{
ABSTRACT
Habitual physical activity and regular exercise training improve cardiovascular health and longevity. A physically active
lifestyle is, therefore, a key aspect of primary and secondary prevention strategies. An appropriate volume and intensity
are essential to maximally benefit from exercise interventions. This document summarizes available evidence on the
relationship between the exercise volume and risk reductions in cardiovascular morbidity and mortality. Furthermore,
the risks and benefits of moderate- versus high-intensity exercise interventions are compared. Findings are presented
for the general population and cardiac patients eligible for cardiac rehabilitation. Finally, the controversy of
excessive volumes of exercise in the athletic population is discussed. (J Am Coll Cardiol 2016;67:316–29)
© 2016 by the American College of Cardiology Foundation.
H
abitual
physical
training
reduce
exercise
in marathons, triathlons, and cycling races over the
disease
past 3 decades (5,6). These individuals typically
(CVD) morbidity and mortality (1,2). The
engage in aerobic exercise volumes and intensities
2008 Physical Activity Guidelines Advisory Com-
well above the 2008 guideline recommendations.
mittee
of
Several recent reports surprisingly suggest that high
moderate-intensity or 75 min/week of vigorous-
volumes of aerobic exercise may be as bad for CVD
intensity aerobic exercise for all U.S. adults (Table 1)
outcomes as physical inactivity (7–10). The public me-
(3), because this exercise volume provides significant
dia has embraced the idea that exercise may harm the
health improvements for most people much of the
heart and disseminated this message, thereby divert-
time. However, only one-half of Americans meet
ing attention away from the benefits of exercise as a
these guidelines (4). In contrast, participation in
potent intervention for the primary and secondary
endurance exercise races has grown in popularity
prevention of heart disease (11). This document will
among the most active individuals, as demonstrated
review the published data on the volume and in-
by the marked increase in the number of participants
tensity of aerobic exercise required for favorable
Report
activity
and
cardiovascular
recommended
150
min/week
The views expressed in this paper by the American College of Cardiology’s (ACC’s) Sports and Exercise Cardiology Leadership
Council do not necessarily reflect the views of the Journal of the American College of Cardiology or the ACC.
From the *Research Institute for Sports and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom;
yDepartment of Physiology, Radboud University Medical Center, Nijmegen, the Netherlands; zDivision of Pediatric Cardiology,
Department of Pediatrics, Baylor College of Medicine, Houston, Texas; xDepartment of Kinesiology, College of Human Sciences,
Iowa State University, Ames, Iowa; kKrannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis,
Listen to this manuscript’s
Indiana; and the {Division of Cardiology, Hartford Hospital, Hartford, Connecticut. Dr. Eijsvogels is supported by a European
audio summary by
Commission Horizon 2020 grant (Marie Sklodowska-Curie Fellowship 655502). Dr. Thompson has received research support from
JACC Editor-in-Chief
the National Institutes of Health, Genomas, Aventis, Roche, Sanofi, Regeneron, Esperion, Amarin and Pfizer; has served as a
Dr. Valentin Fuster.
consultant for Amgen, AstraZeneca, Regeneron, Merck, Genomas, Abbott, Pfizer, Esperion, and Sanofi; has received speaker
honoraria from Merck, AstraZeneca, Regeneron, Sanofi, and Amgen; owns stock in Abbvie, Abbott Laboratories, CVS, General
Electric, Johnson & Johnson, Medtronic, and JA Wiley; and has provided expert legal testimony on exercise-related cardiac events
and statin myopathy. All other authors have reported that they have no relationships relevant to the contents of this paper to
disclose.
Manuscript received October 8, 2015; revised manuscript received November 17, 2015, accepted November 30, 2015.
Eijsvogels et al.
JACC VOL. 67, NO. 3, 2016
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cardiovascular health and will also address the ques-
causally related to lower rates of CVD despite
ABBREVIATIONS
tion as to whether or not there is a volume that in-
the absence of the classical clinical trial.
AND ACRONYMS
creases CVD risk.
The CVD benefits of exercise are likely
mediated via multiple mechanisms. Regular
EXERCISE IN PRIMARY PREVENTION
exercise training improves the CVD risk pro-
GENERAL BENEFITS OF EXERCISE. The health ben-
efits of exercise have been recognized since the
epidemiological studies of Morris et al. (13), who in
the 1950s reported lower rates of coronary heart disease
among
the
conductors
of
London’s
double-decker buses compared with the drivers.
Morris et al. (13) also reported a lower incidence of
coronary heart disease among English postmen
compared with telephone operators working at the
same company. These data were the first to illustrate
an association between habitual physical activity and
cardiovascular health. Many subsequent epidemiological studies confirmed this inverse relationship
between physical activity and CVD (14–16), but none
have proven causation because all such studies are
observational. To date, there are no randomized
clinical trials directly testing whether physical activity prevents CVD. Such a study would require an
enormous sample size and study duration because of
subject crossover among those volunteering for an
“exercise study” and because the progressively lower
rates of primary CVD in the general population would
reduce CVD endpoints. Powell et al. (17) evaluated the
possibly causative relationship between physical activity and cardiovascular disease using the same
criteria used to document a causative relationship
between cigarette smoking and health (18), a relationship also lacking a randomized, controlled clinical
trial. They demonstrated that the relationship between physical activity and CVD was strong, was
consistent among studies, had a graded risk reduction
with increasing exercise volumes, and was coherent
with clinical studies showing a putatively beneficial
effect of exercise on CVD risk factors (17). They
concluded that increasing physical activity was
file by reducing triglycerides and increasing
high-density
lipoprotein
cholesterol
(19),
lowering blood pressure (20), improving
glucose metabolism and insulin sensitivity
CAC = coronary artery
calcification
CVD = cardiovascular disease
HIIT = high-intensity interval
training
IQR = interquartile range
MET = metabolic equivalent of
(21), reducing body weight, and reducing in-
task score
flammatory markers (22). These risk factor
MI = myocardial infarction
improvements explain 59% of the reduction
MICT = moderate intensity
in CVD (23). The remaining 41% may result
continuous training
from improved endothelial function (24),
QOL = quality of life
enhanced vagal tone producing lower heart
SCD = sudden cardiac deaths
rates (25), vascular remodeling including
larger vessel diameters, and an enhanced nitric oxide
bioavailability.
DOSE-RESPONSE RELATIONSHIP BETWEEN PHYSICAL
ACTIVITY AND MORTALITY. The association between
exercise or physical activity and CVD outcome is most
frequently described as a curvilinear relationship
(Figure 1) (26). This indicates that a change from an
inactive to a mild or moderately active lifestyle yields
a relatively large risk reduction, whereas further
increasing exercise volumes produce smaller risk reductions. Thus, any physical activity is better than
none, although higher volumes, even above the 2008
guideline recommendations, appear to further reduce
CVD.
Several studies have examined the minimum volume of aerobic physical activity required to produce
health benefits. The least active, but still effective,
behavior is standing. Standing >2 h/day is associated
with a 10% reduction of all-cause mortality (hazard
ratio [HR]: 0.90; 95% CI: 0.85 to 0.95) compared with
standing <2 h/day (27). Increased standing time was
associated with larger risk reductions, with the
lowest mortality in individuals standing $8 h/day
(HR: 0.76; 95% CI: 0.69 to 0.95), but standing time
could have also included light physical activity, such
as walking, in addition to only standing. The study
T A B L E 1 Examples of Moderate- and Vigorous-Intensity
population included 221,240 Australians age $45
Activities to Achieve 2008 Exercise Guideline Recommendations
years and the results were independent of health
Moderate-Intensity
Aerobic Activities
>150 min/week
317
Amount of Exercise to Reduce CV Events
Vigorous-Intensity
Aerobic Activities
>75 min/week
Brisk walking (>3 miles/h)
Uphill walking or race walking
status and were not altered by sex, age, body mass
index, other physical activity, and sitting time (27).
Similar reductions in all-cause mortality with stand-
Bicycling (<10 miles/h)
Bicycling (>10 miles/h)
ing were observed prospectively in 16,586 Canadians
Water aerobics
Running or jogging
(28), but this study also showed that standing 25%
Tennis (doubles)
Tennis (singles)
and 75% of the time was associated with 18% and 32%
Ballroom dancing
Aerobic dancing
reductions in CVD mortality, respectively (HR: 0.82;
General gardening
Heavy gardening (digging/hoeing)
95% CI: 0.68 to 0.99 and HR: 0.68; 95% CI: 0.50 to
From the Centers for Disease Control and Prevention guidelines (12).
0.92) (28). This dose–response relationship between
standing and CVD mortality informs on the lower end
Eijsvogels et al.
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Amount of Exercise to Reduce CV Events
Importantly, the detrimental effects of sitting appear
F I G U R E 1 The Curvilinear Relationship Between Physical Activity and
to be independent from the benefits of physical ac-
Cardiovascular Risk
tivity (30). Recent studies demonstrate that breaking
up sitting time improves cardiovascular health (31)
High
and glucose homeostasis (32), and replacement of
sitting time effectively reduces all-cause mortality
CARDIOVASCULAR RISK
(33). It is therefore recommended that future primary
Δ
intervention programs target both sedentary behavior
as well as habitual physical activity to maximize the
reduction in cardiovascular risk.
Studies of moderate- and vigorous-intensity ac-
Δ
tivity below the recommended exercise volume
(34–36) confirm substantial health benefits from low
levels of activity. Americans running 51 min/week or
Δ
68% of the recommended volume experienced lower
CVD mortality (HR: 0.45; 95% CI: 0.31 to 0.66) and allLow
cause mortality (HR: 0.70; 95% CI: 0.58 to 0.85)
None
High
compared with nonrunners (34). Similarly, Taiwanese
PHYSICAL ACTIVITY VOLUME
engaging in moderate-intensity exercise 92 min/
A similar increase in physical activity yields different risk reductions across the activity
spectrum. Physical inactivity is associated with the highest risk, whereas high aerobic
week, or 61% of the recommended volume, experienced a reduction in CVD mortality (HR: 0.81; 95% CI:
0.71 to 0.93) and all-cause mortality (HR: 0.86;
exercise volumes are associated with the lowest risk (26).
95% CI: 0.81 to 0.91) compared with their inactive
of the CVD benefit relationship and supports the
concept that even small amounts of physical activity
provide CVD benefit.
An additional benefit of the increase in time
standing and performing light physical activity is the
simultaneous reduction of even less taxing activities
such as sitting. Prolonged sitting increases the risk for
all-cause mortality in a dose-dependent fashion (29).
peers (35). A meta-analysis including 661,137 American
and European men and women also demonstrated
that individuals performing moderate- to vigorousintensity leisure time physical activity at a volume
below 2008 guideline recommendations had a 20%
reduction in CVD mortality (HR: 0.80; 95% CI: 0.77 to
0.84) and all-cause mortality (HR: 0.80; 95% CI: 0.78 to
0.82) compared with inactive control subjects (36).
These data emphasize that even low exercise volumes
can effectively reduce CVD mortality, a message that
F I G U R E 2 The Dose-Response Curve of Physical Activity and Cardiovascular Mortality
able populations to become physically active.
1.0
CVD Mortality (Hazard Ratio)
clinicians should communicate to stimulate vulnerThe volume of aerobic exercise to improve CVD
outcomes maximally is difficult to determine. The
0.8
metabolic equivalent of task (MET) score uses the
intensity of exercise (a multiple of the resting meta-
0.6
bolic rate) from the Compendium for Physical Activities (37) multiplied by an assessment of the
0.4
frequency (sessions/week) and duration (h/week) to
calculate the exercise volume in MET-h/week. We
Wen et al.
0.2
combined data from Taiwanese (35), American, and
Arem et al.
European population studies (36) to assess the dose–
0.0
response relationship between physical activity and
0
20
40
60
80
Physical Activity Volume (MET-h/week)
CVD mortality (Figure 2). Maximal risk reduction for
cardiovascular mortality was found at a volume of
41 MET-h/week. This is 3.5 to 4 greater than the
On the basis of data from the studies of Wen et al. (35) (blue squares) and Arem et al. (36)
(orange circles). The average exercise volume (MET-h/week) was calculated for the ranges
of physical activity that were provided in the study by Arem et al. (36). The maximal risk
recommended volume and equals 547 min/week
of moderate-intensity exercise at 4.5 METs or 289
reduction for cardiovascular mortality was found at an exercise volume of 41 MET-h/week.
min/week of vigorous-intensity exercise at 8.5 METs.
CVD ¼ cardiovascular disease; MET ¼ metabolic equivalent of task score.
Individuals performing exercise at this volume
experienced a 45% lower risk for CVD mortality
Eijsvogels et al.
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Amount of Exercise to Reduce CV Events
(HR: 0.55; 95% CI: 0.46 to 0.66) compared with
compared
inactive control subjects.
moderate-intensity exercise (HR: 0.91; 95% CI: 0.84
with
individuals
performing
only
Only 3.5% of individuals included in the meta-
to 0.98 and HR: 0.87; 95% CI: 0.81 to 0.93, respec-
analysis mentioned exceed the exercise volume that
tively) after adjusting for total volume of moderate-
was associated with maximal health benefits (36).
to vigorous-intensity activities (41). These observa-
These individuals experienced reductions in CVD
tions are consistent with a systematic review of
mortality comparable to the “maximal benefit” group
epidemiological studies and clinical trials demon-
(HR: 0.61; 95% CI: 0.55 to 0.67; and HR: 0.71; 95%
strating a larger reduction in CVD events and
CI: 0.56 to 0.91 for subjects performing 40 to 75
improvement in CVD risk factors for vigorous versus
MET-h/week and >75 MET-h/week, respectively) (36),
moderate intensity physical activity (42).
but this difference was not statistically significant
Interestingly, the dose-response curve between
in part because the small percentage of individuals
physical activity and mortality appears to be different
exercising at this volume creates large confidence
for
intervals. Performing exercise volumes at the upper
(Figure 3). Increasing levels of moderate intensity
end of the physical activity spectrum therefore
physical activity progressively reduces CVD mortality,
appears to be safe because there is no evidence for
whereas the response curve flattens for vigorous
adverse CVD outcomes among these individuals.
physical activity in an excess of 11 MET-h/week (34,35).
DOES INTENSITY MATTER? Moderate-intensity ac-
Similar patterns exist for all-cause mortality, although
tivities are defined as requiring 3.0 to 5.9 METs of
the differences between moderate and vigorous
energy
intensity activity were less pronounced (34–36)
expenditure,
whereas
vigorous
intensity
moderate
versus
vigorous-intensity
exercise
requires $6.0 METs. High-intensity interval training
(Figure 3). These findings indicate that increasing
produces larger improvements in cardiorespiratory
volumes of moderate-intensity exercise are associ-
fitness,
with
ated with further improvements in CVD health,
moderate-intensity, continuous training (38). Higher
whereas for vigorous intensity, lower volumes are
fitness levels are associated with a reduction in CVD
associated with maximal risk reduction.
expressed
as
VO 2max,
compared
(39) and all-cause mortality (40) in a curvilinear
This relationship may be due at least in part to the
fashion. The potential superior health benefits of
repeated observation that vigorous-intensity exercise
vigorous-intensity exercise are supported by epide-
acutely, albeit transiently, increases CVD events
miological data. Australians performing <30% of their
(43–45). A total of 122 sudden cardiac deaths (SCDs),
total physical activity in vigorous exercise, as well as
23 (18.9%) of which were exercise related, occurred in
those performing >30% had reduced mortality rates
a study of 21,481 male physicians (45). The absolute
F I G U R E 3 The Dose-Response Curve of Moderate- and Vigorous-Intensity Physical Activity and Cardiovascular and All-Cause Mortality
1.0
All-Cause Mortality (Hazard Ratio)
CVD Mortality (Hazard Ratio)
1.0
0.8
0.6
0.4
0.2
Moderate intensity PA
Vigorous intensity PA
0.8
0.6
0.4
0.2
Moderate intensity PA
Vigorous intensity PA
0.0
0.0
0
10
20
30
40
Physical Activity Volume (MET-h/week)
50
0
10
20
30
40
50
Physical Activity Volume (MET-h/week)
The dose-response curve of moderate-intensity (solid lines) and vigorous-intensity (dashed lines) physical activity and cardiovascular (left) and all-cause
mortality (right) based on data from the studies of Wen et al. (35) (blue squares), Lee et al. (34) (gray triangles), and Arem et al. (36) (orange circles).
The average exercise volume (MET-h/week) was calculated for the ranges of physical activity that were provided in the study by Arem et al. (36). These figures
demonstrate that vigorous intensity activities already reach a maximum risk reduction at lower exercise volumes, whereas larger volumes of moderate
intensity activities are associated with a further reduction in cardiovascular/all-cause mortality. PA ¼ physical activity; other abbreviations as in Figure 2.
319
320
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Amount of Exercise to Reduce CV Events
risk for a vigorous exercise-related SCD was low at
reductions in body fat and improvements in muscle
1 per 1.42 million hours, but 16.9% higher (95% CI:
strength compared with aerobic exercise alone (51).
10.5% to 27.0%; p < 0.001) than that during low/no
Adding strength training to aerobic programs tends to
physical activity. Despite this acute increase in risk
produce larger increases in cardiopulmonary fitness
during vigorous activity, the relative risk (RR) for SCD
and improvements in quality of life (QOL) in patients
decreased progressively with increasing habitual
with CVD (51). Increased QOL may occur because
vigorous exercise from an RR of 74.1 for those exer-
the increases in exercise capacity and strength
cising vigorously <1 session/week (95% CI: 22.0 to
increase self-confidence and independence after a
249) versus an RR of 18.9 for those exercising vigor-
CVD event.
ously 1 to 4 sessions/week (95% CI: 10.2 to 35.1) versus
an RR of 10.9 for those exercising vigorously $5 sessions/week (95% CI: 4.5 to 26.2) (45). The pattern is
similar for the association between vigorous exertion
and acute myocardial infarction (MI) in the general
population (44). Among 1,228 MI patients, the risk for
a vigorous activity-induced MI was markedly lower
for individuals regularly involved in vigorous activities ($5 sessions/week; RR: 2.4) compared with
sedentary individuals (no sessions/week, RR: 107)
(44). Such results demonstrate that vigorous physical
activity transiently increases the risk for acute cardiac
events, but reduces the overall risk.
In summary, volumes of moderate- and vigorousintensity exercise below the 2008 Physical Activity
Guideline recommendations result in a significantly
lower mortality risk in different populations around
the globe. Increasing volumes of moderate-intensity
exercise result in larger reductions of CVD mortality,
whereas no further reduction in CVD mortality is
observed for volumes of vigorous-intensity exercise
beyond 11 MET-h/week. Finally, there is no evidence
for an upper limit of exercise-induced health benefits.
Every volume of moderate- and vigorous-intensity
aerobic exercise results in a reduction of all-cause
and CVD mortality compared with physical inactivity.
EXERCISE IN SECONDARY PREVENTION
CARDIAC REHABILITATION. Patients with stable angina
pectoris, systolic heart failure, MI, recent cardiac
surgery, or a percutaneous coronary intervention are
eligible for cardiac rehabilitation. Contemporary cardiac rehabilitation programs include not only exercise
training but also nutritional and psychological counseling; weight, blood pressure, lipid, and diabetes
management; and smoking cessation (52). The goal is
to reduce CVD risk via pharmacotherapy, improved
health behavior, and a physically active life-style.
In contrast to the available evidence for primary
prevention, there are randomized clinical trials
assessing the benefits of exercise training and cardiac rehabilitation on CVD in select patient populations. A Cochrane review of 47 randomized
controlled trials including 10,794 coronary heart
disease patients (53) demonstrated that cardiac
rehabilitation reduced all-cause (RR: 0.87; 95% CI: 0.75
to 0.99) and CVD mortality (RR: 0.74; 95% CI: 0.63
to 0.87) after >1 year of follow-up. Furthermore, a
decrease in hospital admissions was found in the
cardiac rehabilitation versus the standard care group
within 1 year of follow-up (RR: 0.69; 95% CI: 0.51 to
0.93). A meta-analysis including 6,111 post-MI patients
from 34 randomized controlled clinical trials showed
similar results, with exercise-based rehabilitation
demonstrating a lowered risk for all-cause mortality
(odds ratio [OR]: 0.74; 95% CI: 0.58 to 0.95), CVD
CURRENT
GUIDELINE
RECOMMENDATIONS. Exer-
mortality (OR: 0.61; 95% CI: 0.40 to 0.91), cardiac
cise is a key component in the management of pa-
mortality (OR: 0.64; 95% CI: 0.46 to 0.88), and rein-
tients with most established CVD because it reduces
farction (OR: 0.54; 95% CI: 0.38 to 0.76) (54).
recurrent CVD events. Guidelines from the American
A Cochrane review of 33 randomized clinical trials
College of Cardiology and American Heart Association
including 4,740 patients with predominantly systolic
include specific recommendations for diverse pop-
heart failure (55) demonstrated that cardiac reha-
ulations of cardiac patients (Table 2) (46–50). The
bilitation and exercise training reduced all-cause
recommend exercise volume is generally similar to
(RR: 0.75; 95% CI: 0.62 to 0.92) and heart failure–
that for healthy adults: 30 to 60 min/day of
specific (RR: 0.61; 95% CI: 0.46 to 0.80) hospitalization
moderate-intensity aerobic activities. Exercise can be
rates. QOL also improved more in the cardiac rehabil-
performed as a part of a clinical rehabilitation pro-
itation patients. All-cause mortality was not different
gram or at home and in the community. Patients are
between the exercise-based cardiac rehabilitation and
advised to include resistance exercise training to
no exercise control arms at 1 year of follow-up
maintain strength and muscle mass. A meta-analysis
(RR: 0.93; 95% CI: 0.69 to 1.27), but trended toward
of 504 studies suggests that the combination of
significance in follow-up >1 year (RR: 0.88; 95% CI:
aerobic and resistance exercise produces greater
0.75 to 1.02) (55).
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Amount of Exercise to Reduce CV Events
T A B L E 2 Physical Activity and/or Exercise Recommendations for Cardiac Patient Populations
Class of
Recommendation
Level of
Evidence
I
C
Exercise training (or regular physical activity) is recommended as safe and effective for patients with
heart failure who are able to participate to improve functional status.
I
A
Cardiac rehabilitation can be useful in clinically stable patients with heart failure to improve functional
capacity, exercise duration, health-related quality of life, and mortality.
IIa
B
All eligible patients with non–ST-segment elevation acute coronary syndromes should be referred to a
comprehensive cardiovascular rehabilitation program either before hospital discharge or during the
first outpatient visit.
I
B
Detailed instructions for daily exercise, patients should be given specific instruction on activities (e.g.,
lifting, climbing stairs, yard work, and household activities) that are permissible and those to avoid.
Specific mention should be made of resumption of driving, return to work, and sexual activity.
I
B
Exercise-based cardiac rehabilitation/secondary prevention programs are recommended for patients
with STEMI.
I
B
A clear, detailed, and evidence-based plan of care that promotes medication adherence, timely
follow-up with the healthcare team, appropriate dietary and physical activities, and compliance with
interventions for secondary prevention should be provided to patients with STEMI.
I
C
Medically supervised programs (cardiac rehabilitation) and physician-directed, home-based programs
are recommended for at risk patients at first diagnosis.
I
A
For all patients, the clinician should encourage 30 to 60 min of moderate-intensity aerobic activity, such
as brisk walking, at least 5 days and preferably 7 days per week, supplemented by an increase in daily
life-style activities (e.g., walking breaks at work, gardening, household work) to improve
cardiorespiratory fitness and move patients out of the least-fit, least-active, high-risk cohort
(bottom 20%).
I
B
For all patients, risk assessment with a physical activity history and/or an exercise test is recommended
to guide prognosis and prescription.
I
B
IIa
C
Recommendations for Cardiac Patient Populations (Ref. #)
Congenital heart disease (46)
Exercise prescription, guidelines for exercise, and athletic participation for patients with congenital heart
disease should reflect the published recommendations of the 36th Bethesda Conference report.
Heart failure (47)
Non–ST-segment elevation acute coronary syndromes (48)
STEMI (49)
Stable ischemic heart disease (50)
It is reasonable for the clinician to recommend complementary resistance training at least 2 days
per week.
STEMI ¼ ST-segment elevation myocardial infarction.
HF-ACTION (Heart Failure: A Controlled Trial
Patients receiving exercise training also reported an
Investigating Outcomes of Exercise Training) exam-
earlier and larger improvement in self-reported health
ined the effect of exercise training in 2,331 pa-
status, which persisted over time (57).
tients
ejection
THE VOLUME AND INTENSITY OF AEROBIC EXERCISE
fractions <35%. Subjects participated in 12 weeks of
TRAINING FOR SECONDARY PREVENTION. Most cardiac
supervised thrice-weekly exercise training followed
rehabilitation studies and programs used a re-
by an at-home training program. The investigators
latively standard exercise protocol. Subjects gener-
sought to enhance adherence to the home exercise by
ally exercised 3 weekly for 30 to 40 min/session
providing treadmills or stationary cycles to partici-
at heart rates equal to 60% to 85% of their maximal
pants. Despite such efforts, adherence to the exercise
value or age-estimated maximal value. The risk
training program was low and the average increase in
of
maximal oxygen uptake was only 0.7 ml/kg/min
individuals with CVD was initially estimated at 6 to
with
systolic
heart
failure
and
cardiac
arrest
during
vigorous
exercise
in
(interquartile range [IQR]: –1.0 to 2.5 ml/kg/min), a
164 greater than their risk at rest (58). The risk of a
value lower than most prior, smaller studies of exer-
cardiac event during contemporary cardiac rehabili-
cise training in this population. Heart failure patients
tation is low: estimated at only 1 cardiac arrest
receiving exercise training had a reduced incidence of
per 116,906 patient-hours of participation and 1
cardiovascular mortality and heart failure hospitali-
fatality per 752,365 patient-hours (59). These event
zation compared to the nonexercise training usual care
rates apply to supervised cardiac rehabilitation where
group (HR: 0.87; 95% CI: 0.75 to 1.00) (56). After
trained
correction for highly prognostic baseline factors
administer resuscitation if needed. Comparing the
and heart failure etiology, these findings became sta-
cardiac arrest and mortality rates suggests that the
tistically significant (HR: 0.85; 95% CI: 0.74 to 0.99).
fatality
personnel
rate
can
would
be
monitor
6-fold
symptoms
higher
and
without
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322
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Amount of Exercise to Reduce CV Events
successful resuscitation performed by the rehabilita-
Norwegian patients with coronary heart disease
tion staff.
observed no attenuated mortality risk reduction in
There are few studies examining the effect of ex-
the most active group (Central Illustration). These
ercise volume on CVD outcomes in cardiac patients,
current studies are limited by their observational
because most studies used standard and similar ex-
nature, their use of self-reported activity patterns,
ercise training protocols. Data from the HF-ACTION
and a potential selection bias of participating sub-
trial suggest a curvilinear response between the vol-
jects. The possibility that high levels of exercise
ume of exercise and the subsequent risk for cardio-
attenuate the reduction in CVD events warrants
vascular events during 28 months of follow-up (60).
additional examination because of the widespread
$5
perception that more of a good thing is better. Hence,
survival
the extrapolation of these observations is limited and
Heart
failure
MET-h/week
patients
had
a
performing
higher
exercise
event-free
compared with those performing lower volumes of
may only be of concern in a minority of patients.
exercise (i.e., <1, 1 to 3, or 3 to 5 MET-h/week). How-
Despite these concerns about the volume and in-
ever, after correction for peak VO 2 values, a J-shaped
tensity of exercise in CVD patients, several studies
curve appeared, with the largest risk reductions in
have explored strategies to optimize the effects of
patients exercising 3 to 7 MET-h/week and less benefit
cardiac rehabilitation using high-intensity interval
for patients exercising $7 MET-h/week (60).
training (HIIT), modeled after athletic training pro-
Several studies in CVD subjects exercising in un-
grams. HIIT was introduced into cardiac rehabilitation
supervised settings reinforce the hypothesis that high
in 2007 and typically consists of a 10-min warm-up at
volumes of exercise may be deleterious in this patient
60% to 70% of peak heart rate, followed by 4 4-min
group. The National Runners’ and Walkers’ Health
intervals at 90% to 95% of peak heart rate separated
studies of Williams et al. (10) recorded the baseline
by 3-min active pauses at 50% to 70% of peak heart
exercise habits and health outcomes of 2,377 subjects
rate (63). The exercise session is ended by a 3-min
who were self-identified as heart attack survivors at
cool down at 50% to 70% of peak heart rate (Figure 4).
baseline. A total of 526 died over an average follow-
Heart failure patients receiving HIIT demonstrated
up of 10.4 years; 71.5% died due to CVD. CVD
a 46% improvement in cardiorespiratory fitness
mortality decreased progressively with increasing
(VO 2peak) compared with only a 14% improvement in
amounts of exercise to a maximum mortality reduc-
patients expending the same amount of energy dur-
tion of 63% in those running or walking at a volume of
ing
38 to 50 MET-h/week compared with the least active
training (MICT) consisting of a 47-min exercise bout
group (<8 MET-h/week). In the most active exer-
at 70% to 75% of peak heart rate (Figure 4) (63).
traditional,
moderate
intensity
continuous
cisers, however, those running >7.1 km a day or
A meta-analysis including 229 patients with coro-
walking briskly >10.7 km a day, the reduction in CVD
nary artery disease demonstrated that HIIT produced
mortality was only 12%, and was not different from
a larger increase in VO 2peak (weighted mean differ-
the least active group (Central Illustration).
ence: 1.53 ml/kg/min; 95% CI: 0.84 to 2.23) compared
These data from Williams et al. (10) show an
with MICT (64). Similarly, a meta-analysis comparing
attenuation of mortality risk reductions in patients
changes in fitness in cardiac rehabilitation trials for
with the highest levels of exercise. Studies by both
heart failure that included 5,877 patients found larger
Wannamethee et al. (61) and Mons et al. (9) also show
improvements in VO2peak for training programs using
an apparent reduction in the benefit of exercise in the
higher exercise intensities (65). Moreover, fewer
most active subjects. Among 772 British patients with
heart failure patients withdrew from the studies in
coronary heart disease (61), lightly and moderately
the highest exercise intensity groups.
active patients had a significantly lower all-cause and
The greater increase in cardiorespiratory fitness
CVD-related mortality risk compared with inactive
with more intense exercise training in CVD patients
patients, whereas moderately to vigorously active
does not necessarily mean that the more intense
patients did not (Central Illustration). Similarly, Mons
training regimens will increase survival. There are
et al. (9) found that among 1,038 German coronary
also potential risks to more intense exercise in CVD
heart disease patients, patients exercising 2 to 4 ses-
patients especially if performed in the absence of
sions/week demonstrated the lowest all-cause (7.6
trained medical personnel. A comparison of adverse
per 1,000 person-years) and cardiovascular mortality
CVD events between MICT and HIIT in 4,846 cardiac
(4.5 per 1,000 person-years), whereas higher or lower
patients revealed event rates of 1 per 129,456 and
exercise frequencies were associated with higher
1 per 23,182 patient-hours, respectively (66). These
mortality rates (Central Illustration). In contrast, the
data suggest a higher risk for adverse CVD outcomes
examination
with HIIT, but there were only 1 fatal cardiac arrest
by
Moholdt
et
al.
(62)
of
3,504
Eijsvogels et al.
JACC VOL. 67, NO. 3, 2016
JANUARY 26, 2016:316–29
Amount of Exercise to Reduce CV Events
CENTRAL I LLU ST RAT ION
The Amount of Exercise to Reduce Cardiovascular Events in Cardiac Patient Populations
A. Williams et al.
B. Wannamethee et al.
Mortality Risk (Hazard Ratio)
Mortality Risk (Hazard Ratio)
2.0
1.5
1.0
0.5
0.0
<8
8-13
13-25
25-38
38-50
Inactive
>50
Physical Activity Volume (MET-h/week)
Light
Moderate
Mod./Vig.
Physical Activity Volume (Activity Score)
C. Mons et al.
D. Moholdt et al.
Mortality Risk (Hazard Ratio)
Mortality Risk (Hazard Ratio)
12
10
8
6
4
2
0
0
≤1
2-4
5-6
7
Physical Activity Volume (Sessions/Week)
0
<1
1
2-3
≥4
Physical Activity Volume (Sessions/Week)
All-cause Mortality
CVD Related Mortality
Eijsvogels, T.M.H. et al. J Am Coll Cardiol. 2016; 67(3):316–29.
The dose-response curve of physical activity and all-cause (red lines) and cardiovascular mortality (blue lines) among cardiac patient populations. Data were extracted
from the studies of (A) Williams et al. (10), (B) Wannamethee et al. (61), (C) Mons et al. (9), and (D) Moholdt et al. (62). CVD ¼ cardiovascular disease; MET ¼ metabolic
equivalent of task score; Mod./Vig. ¼ moderate to vigorous.
and 2 nonfatal cardiac arrests with MICT and HIIT,
health benefits in cardiac patients, with risk rates
respectively, so there were too few events and
returning to the level of inactive peers. Moderate-
insufficient power to compare risk.
intensity exercise at volumes comparable to guide-
Taken together, referral to an exercise rehabilitation
lines (46–50) should therefore be recommended for
program is recommended for cardiac patients, because
cardiac patients by their clinicians to achieve maximal
participants benefit from a reduced risk for future
cardiovascular benefits.
cardiovascular events and mortality. Supervised HIIT
protocols yield larger health improvements than MICT
THE CONTROVERSY OF EXCESSIVE EXERCISE
protocols. The risk for cardiac arrest and SCD during
exercise is low but present. High-intensity activities
The amount of habitual exercise training required to
and high weekly exercise volumes may attenuate the
be a successful endurance athlete is markedly higher
323
Eijsvogels et al.
324
JACC VOL. 67, NO. 3, 2016
JANUARY 26, 2016:316–29
Amount of Exercise to Reduce CV Events
F I G U R E 4 Example of a HIIT Protocol Versus an MICT Protocol in Cardiac Rehabilitation
Exercise Intensity (% HRmax)
90
elevated for 4 to 10 days in acute MI patients in
conjunction with acute electrocardiogram changes
HIIT
MICT
100
up to 50 the upper limit of normal and remain
and imaging evidence of ischemia (80). It is therefore
hypothesized that troponin elevations in athletes
80
represent a physiological rather than a pathological
70
phenomenon (81), potentially caused by troponin
60
leaks from the cytosol of cardiomyocytes due to an
50
exercise-induced increase in membrane permeability.
40
Small cardiac foci of late gadolinium enhancement
30
have been found during cardiac magnetic resonance
20
imaging in some (68,82,83), but not all (84,85) studies
10
of endurance athletes. These observations provide
0
0
5
10
15
20
25
30
35
40
45
50
Training Duration (min)
evidence of myocardial fibrosis, possibly increasing
the risk of cardiac arrhythmia and mortality (86,87).
The presence of myocardial fibrosis was observed in
12% to 50% of the athletes and was associated with
Both exercise protocols are isocaloric (63). HIIT ¼ high-intensity interval training;
longer endurance exercise participation and higher
HRmax ¼ maximal heart rate; MICT ¼ moderate-intensity continuous training.
years of training and number of completed marathons
(68,82,83). Fibrosis was frequently found where the
right ventricle inserts into the septum, a location that
than that required for cardiovascular health. Multiple
is rarely observed in ischemic cardiac patients.
studies
potentially
Interestingly, comparable patterns are observed in
adverse cardiovascular outcomes in athletes. For
hypertrophic cardiomyopathy patients (88). Simi-
example,
exercise-
larly, faint late gadolinium enhancement has been
induced elevations in cardiac troponin levels (67),
observed at the superior and inferior insertion points
evidence of myocardial fibrosis (68), post-exercise
of the right and left ventricles of patients whose right
cardiac dysfunction (69), an increased incidence of
ventricle was forced to produce systemic pressures
arrhythmias (70), accelerated coronary artery calcifi-
after atrial redirection surgery for transposition of the
have
some
reported
unexpected,
athletes
demonstrate
cations (71), and an increased risk for cardiovascular
great vessels (89). This suggests a nonischemic
morbidity and mortality at high amounts of exercise
etiology for the fibrosis found in athletes and that it is
compared with light to moderate amounts of exercise
possibly due to the increase in mechanical stress on
(7,8). These observations among marathon runners,
the right ventricle during exercise (90). Nevertheless,
triathletes, cross-country skiers, and cyclists raise the
athletes with late gadolinium enhancement demon-
question of whether such athletes may experience
strated a worse event-free survival compared with
potentially detrimental cardiac side effects from their
those without imaging abnormalities (75% vs. 99%;
exercise habits (72).
p < 0.001) in 1 study (82).
cardiac
Post-exercise decreases in left and right ventricular
troponin T and I are observed in athletes participating
function are observed in some endurance athletes,
in running races (15, 21, or 42 km) (73), triathlons (74),
with a larger decrement in the right versus left ventricle
endurance cycling (75), and ultra-endurance races
(76,91). The magnitude of the reduction in cardiac
(76), but also in individuals from the general popu-
function is associated with longer exercise duration
Exercise-induced,
acute
elevations
in
lation performing prolonged walking exercise (77).
(68) and lower training status (92). This cardiac
Post-exercise troponin concentrations are related to
dysfunction is mild and typically recovers within 48 h
the covered distance (73) and exercise intensity (78),
after exercise cessation (93). Exercise-induced right
and exceed the upper reference limit for an acute MI
ventricular dysfunction appears to be more pro-
in >50% of the athletic population (67). Although
nounced in athletes with ventricular arrhythmias
these findings suggest cardiac damage due to exercise
compared with healthy athletes (94). Whether athletes
performance, the kinetics of troponin release are
with a transient decline in cardiac function are at risk
different between patients and athletes. Athletes
for future arrhythmias is currently unknown.
demonstrate modestly elevated peak troponin levels
The association between physical activity patterns
that normalize within 72 h post-exercise in absence
and incident atrial fibrillation is complicated. More
of any signs or symptoms of ischemia (79). In
leisure-time activity, greater walking distance, faster
contrast, peak troponin concentrations can increase
walking pace, and higher cardiorespiratory fitness
Eijsvogels et al.
JACC VOL. 67, NO. 3, 2016
JANUARY 26, 2016:316–29
Amount of Exercise to Reduce CV Events
were associated with a graded risk reduction for
disease, even in women performing daily strenuous
atrial fibrillation in the Cardiovascular Health Study
exercise (RR: 0.89; 95% CI: 0.84 to 0.93) (8). An
(N ¼ 5,446) and Henry Ford Exercise Testing (FIT)
important caveat of this study was the higher smoking
Project (N ¼ 64,561) (95,96). In contrast, a meta-
prevalence among daily strenuous exercisers (25.6%)
analysis (N ¼ 1,550) reported a 5-fold increase in the
compared with all other exercise groups (13.7%
relative risk for atrial fibrillation in athletes (OR: 5.3;
to 15.5%). This may partially explain the absence
95% CI: 3.6 to 7.9) compared with the general popu-
of exercise-induced health benefits in the most
lation (97). Also, a large Swedish study (N ¼ 52,755)
active individuals. A Danish study including joggers
confirmed these findings and observed a higher
(n ¼ 1,098) and nonjoggers (n ¼ 3,950) reported similar
fibrillation
participants
findings for all-cause mortality (7). Arbitrarily classi-
completing $5 versus 1 Vasaloppet cross-country ski-
fied “light” joggers (HR: 0.22; 95% CI: 0.10 to 0.47) had
races (HR: 1.29; 95% CI: 1.04 to 1.61) and in those with
a lower mortality risk compared with nonjoggers,
faster finishing times (100% to 160% vs. >240% of
whereas mortality rates in “moderate” (HR: 0.66;
winning time; HR: 1.20; 95% CI: 0.93 to 1.55). A po-
95% CI: 0.32 to 1.38) and “strenuous” joggers (HR: 1.97;
tential explanation for these apparently contradictory
95% CI: 0.48 to 8.14) were comparable to nonjoggers
findings is that the relationship between physical
(7). For any other classification of physical activity
activity may be U-shaped, with moderate amounts of
(quantity, frequency, or pace), however, the most
exercise decreasing but large volumes of exercise
active group always demonstrated a lower mortality
increasing atrial fibrillation risk (96,98).
compared with nonjoggers. Other important study
incidence
of
atrial
in
The physically active lifestyle of athletes does not
limitations include the low number of subjects in the
prevent the development of central and peripheral
strenuous jogger group and the fact that inclusion in
atherosclerosis (99). In fact, greater coronary artery
the nonjoggers group allowed participants to walk or
calcification (CAC) scores have been found in German
bike up to 2 h/week (102). Given the methodological
marathon runners (median 36; IQR: 0 to 217)
limitations of these 2 studies, it is premature to
compared with control subjects (median 12; IQR: 0 to
conclude that high exercise volumes, compared with
78) matched for age and Framingham risk score (71),
light to moderate volumes, could increase CVD risk.
but this difference disappeared when the authors
The exercise-induced changes in cardiac structure
corrected for age only (median 38; IQR: 3 to 187).
and function are often related to the volume (late-
Alternatively, the elevated CAC scores may be the
gadolinium enhancement, cardiac dysfunction, and
result of plaque stabilization, as a higher CAC density
CAC) and intensity (troponin release and atrial fibril-
is protective for future cardiovascular outcomes
lation) of activities performed by athletes. For most
(100). This hypothesis aligns with epidemiological
observations, the long-term clinical implications are
observations of reduced cardiovascular morbidity and
currently unknown, but it is unlikely that these are
mortality in athletes compared with sedentary con-
similar to risk classifications in CVD patient pop-
trol subjects (101).
ulations. For example, recreational marathon training
Two recent epidemiological studies reported a U-
has been shown to have a positive effect on several
shaped relationship between aerobic exercise vol-
determinants of cardiovascular risk (103). Also, life-
umes and cardiovascular morbidity (8) and mortality
long patterns of “committed” exercise (4 to 5
(7) in the general population. A British study
sessions/week) and “competitive” Masters-level ath-
(N ¼ 1,119,239) showed a lower incidence of cerebro-
letes prevents most of the age-related left ventricular
vascular disease (RR: 0.81; 95% CI: 0.78 to 0.84) and
stiffening changes implicated in the pathophysiology
venous thromboembolism (RR: 0.83; 95% CI: 0.79 to
of many cardiovascular disorders (104). Furthermore,
0.87) in women performing 2 to 3 sessions/week
leisure-time runners have lower all-cause (HR: 0.70;
of strenuous activities compared with inactive con-
95% CI: 0.64 to 0.77) and cardiovascular mortality
trol subjects, but these health benefits disappeared
rates (HR: 0.55; 95% CI: 0.46 to 0.65) compared with
in women performing daily strenuous activities
nonrunners (34). These observations are not limited
(RR: 0.96; 95% CI: 0.89 to 1.04; and RR: 1.08; 95% CI:
to amateur athletes, but include elite athletes, who
0.99 to 1.17, respectively) (8). In contrast, daily ac-
were engaged in high volumes of vigorous exercise
tivities regardless of the exercise intensity did reduce
for many years, yet demonstrated a 3- to 6-year in-
the incidence of cerebrovascular disease (RR: 0.88;
crease in life expectancy compared with control
95% CI: 0.86 to 0.91) and venous thromboembolism
subjects from general (105–107) and military (108)
(RR: 0.96; 95% CI: 0.93 to 1.00) compared with inac-
populations. Mortality risk reductions were larger
tive control subjects. Also, any volume of (strenuous)
for older athletes and those who participated in
exercise reduced the risk for incident coronary heart
multiple races (101). These findings suggest that
325
326
Eijsvogels et al.
JACC VOL. 67, NO. 3, 2016
JANUARY 26, 2016:316–29
Amount of Exercise to Reduce CV Events
athletes performing exercise volumes at the upper
athletes, is that the benefits of exercise training
end of the physical activity spectrum do not demon-
outweigh the risks. There may also be small subsets of
strate an increased risk for adverse cardiovascular
the population with genetic predispositions to cardiac
outcomes on a population level.
disease for whom vigorous exercise is not beneficial
Even though exercise and exercise training appears
and may even be deleterious, although this repre-
to benefit the majority of people, there may be in-
sents a very small subset of patients. Moreover, the
dividuals with genetic predisposition for cardiac dis-
issue for most developed countries and the majority
ease in whom exercise training is not beneficial.
of their citizens is not concern about too much exer-
Physically active individuals with genetic defects in
cise, but rather the absence of any exercise among
the desmosomal proteins associated with right ven-
most of the population and among patients with CVD.
tricular cardiomyopathy presented earlier in life and
For example, only 62% of 58,269 post-infarction
had signs of more aggressive disease than less phys-
patients were referred to cardiac rehabilitation
ically active individuals with similar genetic muta-
at
tions (109). Whether similar patterns exist for other
attended $1 cardiac rehabilitation session and only
genetic mutations is worthy of investigation.
5.4% completed $36 sessions. This may reflect, in
(110),
whereas
only
23%
despite the evidence that cardiac rehabilitation saves
This review demonstrates that even small amounts of
physical activity, including activities such as standing, are associated with lower CVD risk. Exercise
volumes of 150 min/week of moderate-intensity or 75
min/week of vigorous-intensity aerobic exercise,
such as recommended in the 2008 Physical Activity
Advisory
discharge
part, a lack of clinician enthusiasm for such programs
CONCLUSIONS
Guidelines
hospital
Committee
Report,
further
lives. The available evidence should prompt clinicians to strongly recommend low and moderate exercise training for the majority of our patients.
Equally important are initiatives to promote population health at large through physical activity across
the life span, as it modulates behavior from childhood
into adult life.
reduce CVD mortality. The possibility that too much
exercise training could produce deleterious cardiac
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
effects including myocardial fibrosis, coronary calci-
Paul D. Thompson, Division of Cardiology, Hartford
fication, and atrial fibrillation is interesting and
Hospital, 85 Jefferson Street, Suite #704, Hartford,
worthy of scientific investigation; however, overall
Connecticut
the results, even for very active, life-long endurance
hhchealth.org.
06102.
E-mail:
Paul.Thompson@
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KEY WORDS athletes, cardiac patients,
coronary artery disease, health, heart failure,
longevity, mortality, myocardial infarction,
physical activity
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